The epidermal growth factor receptor (EGFR) is overexpressed on the surface of the vast majority of pancreatic adenocarcinomas.

Preclinical studies of small molecule inhibitors of EGFR have found single agent activity, as well as activity in conjunction with gemcitabine, in pancreatic cancer xenografts.

The authors of this study sought to investigate the use of gemcitabine (G) and erlotinib (E; brand name Tarceva®) as combination treatment in patients (pts) with locally advanced (LA) and metastatic pancreatic cancer.

Materials and Methods

Phase III placebo-controlled, multiinstitutional, randomized trial

569 pts with LA or metastatic pancreatic adenocarcinoma were randomized to one of two arms:

Arm 1 = G + E (n = 285)

Arm 2 = G + placebo (n= 284)

Pts were permitted to have prior history of local radiation therapy, but NO prior chemotherapy was allowed

The combination of complete response, partial response, and stable disease was 59% in the E arm vs. 49.4% in the placebo arm.

QOL was difficult to measure, with no clear differences between the two arms.

EGFR positivity vs. negativity did not predict for better survival or response to E.

The presence of a rash did predict for better survival outcomes (HR = 0.71 with garde 2+ rash).

The combination of G and E was well tolerated overall, with no significant increase in hematologic, renal, or hepatic toxicity compared to placebo.

There was increased grade 1-2 rash, stomatitis, and diarrhea in the E arm, as expected given E's side effect profile.

Author's Conclusions

G and E is a superior regimen to the use of G alone in the treatment of LA and metastatic pancreatic cancer.

This therapeutic combination results in a 25% OS improvement, with better tumor control and PFS.

The incremental toxicity of the two agents is modest compared to single-agent G.

EGFR status by immunohistochemistry is not predictive of survival.

Development of grade 2 or higher skin rash did in fact predict for better survival with G and E.

Clinical/Scientific Implications

Earlier today (11/2/05), the US Food and Drug Administration (FDA) announced the approval of erlotinib in combination with gemcitabine chemotherapy for the treatment of advanced pancreatic cancer patients who have not received prior chemotherapy. This decision is based directly on the results of this very important trial conducted by Dr. Malcom Moore and colleagues. Erlotinib is the first drug to show a significant overall survival improvement when used with gemcitabine chemotherapy as initial treatment for pancreatic cancer in a phase III setting. (Erlotinib has already been approved for use in patients with non-small cell lung cancer whose disease has progressed despite prior chemotherapy.) For a disease as challenging as pancreatic cancer, strides in therapy are immediately welcomed, as such strides have been few and far between. Also, this study emphasizes the value of EGFR targetting in pancreatic cancer.

However, critics warn that while the benefit seen here is statistically significant, it ultimately translates to a survival gain of only 12.8 days. Thus, some question the true meaningfulness of this gain, especially in light of erlotinib's expense. When considering this viewpoint, the excitement over this study and today's FDA announcement can be somewhat blunted. If nothing else, it serves to remind all of us that while this study represents statistically significant progress, the great need for better therapies and improved clinical outcome in this highly fatal disease still remains.

Current ongoing pancreas cancer trials are investigating the combination of gemcitabine and various agents, including: capecitabine, oxaliplatin, cetuximab, and bevacizumab. The results of these studies are eagerly awaited.